WO2008041240A1 - Procédé de préparation de (s)-pramipexole et de ses intermédiaires - Google Patents

Procédé de préparation de (s)-pramipexole et de ses intermédiaires Download PDF

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Publication number
WO2008041240A1
WO2008041240A1 PCT/IN2007/000017 IN2007000017W WO2008041240A1 WO 2008041240 A1 WO2008041240 A1 WO 2008041240A1 IN 2007000017 W IN2007000017 W IN 2007000017W WO 2008041240 A1 WO2008041240 A1 WO 2008041240A1
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formula
pramipexole
diamino
sodium
benzothiazole
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PCT/IN2007/000017
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English (en)
Inventor
Dharmeshkumar Arvindbhai Patel
Rajiv Kumar
Shriprakash Dhar Dwivedi
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Cadila Healthcare Limited
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Publication of WO2008041240A1 publication Critical patent/WO2008041240A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention relates to an improved process for the preparation of (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole of formula (II) useful in the preparation of pramipexole or (S)-2,6-amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) and its pharmaceutically acceptable salts or solvates thereof.
  • the present invention further provides a process for the preparation of Pramipexole and its pharmaceutically acceptable salts, hydrates, solvates thereof.
  • 2-amino-6-(substituted)amino-4,5,6,7-tetrahydrobenzothiazoles are known pharmaceutically active agents.
  • the tetrahydrobenzothiazole derivatives are taught to be useful in treating schizophrenia, Parkinson's disease or Parkinsonism, and/or hypertension.
  • Pramipexole is the commercial product marketed, in a form of a dihydrochloride salt in a peroral formulation, under several brand names e.g. Mirapexin[TM].
  • the compound of formula (I) has one symmetric carbon and they may exist either as a single enantiomer or in a mixed or racemic form.
  • the pharmacological activity of compounds of formula (I) is generally connected only or mainly with one isomer thereof. Accordingly, the dopaminergic activity of the (S) isomer is twice as high as that of the (R) enantiomer.
  • the synthesis of pramipexole by the above process yields R,S( ⁇ )-2 ⁇ amino-6- propylamino-4,5,6,7-tetrahydrobenzothiazole.
  • the above-mentioned acknowledge that the produced racemic compound may be resolved into single enantiomers by classical methods such as chromatography on a chiral phase or fractional crystallization of a salt with an optically active acid.
  • the S(-)-enantiomer of pramipexole was disclosed and characterized therein, no information is provided how it was prepared; i.e. whether it was prepared by a resolution of racemic pramipexole of form some optically active precursor. Further, no information is provided on how to produce the S(-)- enantiomer of pramipexole.
  • WO 2006/003677 Al discloses the improved process the preparation of biologically active tetrahydrobenzothiazole derivative.
  • the patent application discloses the process that has tried to solve the problems of prior art. However, much improvement over the prior art process has still been achieved.
  • the process discloses the formation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole via an isolated bromo intermediate, which on reaction with thiourea gets converted to tetrahydrobenzothiazole.
  • the isolation of bromo intermediate can also be avoided.
  • the halogenation of the protected cyclohexanone derivative is performed in presence of Lewis acid catalysts like AICI 3 , ZnCl 2 or SnCl 2 etc. which will give aluminous waste though increase the yield during the halognation reaction.
  • the overall steps of the reaction will increase by performing isolation and work up for bromo intermediate.
  • US 6,727,637 B2 discloses the monobasic acid addition salts and the mixed salts of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole wherein the monobasic acid includes hydrochloric, hydrobromic, hydroiodic, nitric, benzoic, acetic, methane sulfonic, ethane sulfonic, trifluromethane sulfonic, benzene sulfonic, and p- toluene sulfonic acids.
  • patent US '637 B2 discloses the formation of mixed salts like of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrochloride monotartrate, of 2-amino-6-propylamino -4,5,6,7- tetrahydrobenzothiazole monohydrobromide monotartrate or of 2-amino-6- propylamino-4,5,6,7-tetrahydrobenzothiazole. monomethane sulfonate dibenzoyl-D- tartrate.
  • US 6,770,761 B2 also discloses the process for preparation of 2-amino-6(alkyl)- amino-4,5,6,7-tetrahydrobenzothiazoles which includes the bromination of 1,4- cyclohexadione by bromine in an alcoholic solvent, followed by treatment of the reaction mixture with thiourea or N-acylthiourea and isolation of compound (A), that is further treated with an amine R 1 -NH 2 or a chiral amine to get an imine intermediate and reducing it by reaction with said reducing agent or by hydrogenation, to yield the compound of formula (B)
  • polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x- ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles.
  • polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
  • X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
  • polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. ScL, 58, 911 (1969); and J. K. Haleblian, J. Pharm. ScL, 64, 1269 (1975), all of which are incorporated herein by reference.
  • the present invention relates to provide a simple, cost effective, non-hazardous and easily scaleable at large commercial production process for preparation of (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole of formula (JI) and Pramipexole dihydrochloride of formula
  • the present invention provides an improved process for preparation of (S)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole of formula (II), which is an useful intermediate for the preparation of Pramipexole or (S)-2,6-amino-6-(n-propylamino)- 4,5,6,7-tetrahydro benzothiazole of formula (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof.
  • a crystalline form of pramipexole dihydrochloride monohydrate in its preferred form characterized by x-ray powder diffraction patter having 20 6.50, 12.00, 12.96, 19.48, 21.34, 24.19, 28.47, 32.74 ⁇ 0.2° as the characteristic peaks and showing the DSC endotherm at 300 0 C (decomposition);
  • the present invention further provides an improved process for the preparation of Pramipexole dihydrochloride monohydrate. BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. I is a Differential Scanning Calorimetry (DSC) theromgram of the Pramipexole dihydrochloride monohydrate
  • FIG. II is an X-ray powder diffractogram (XRD) of the Pramipexole dihydrochloride monohydrate, measured on Rigaku D/Max-2200/PC Diffractometer with Cu K alpha- 1 radiation source.
  • XRD X-ray powder diffractogram
  • an improved process for the preparation of Pramipexole its pharmaceutically acceptable salts, solvates, hydrates thereof which comprises the steps of; a) treating a compound 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole (III)
  • 2-amino-6-phthalimido-4,5,6,7- tetrahydrobenzothiazole of formula (III) is treated with a base at a ratio of 1:1.5-1:5 in an aqueous medium to give racemic 2,6-diamino-4,5,6,7-tetrahydro-l,3-benzothiazole of formula (IV).
  • the reaction is preferably carried out at about 30 to 6O 0 C.
  • said base used in step (a) is a deprotecting reagents of phthalimido groups like hydrazine, phenyl hydrazine, sodium sulphide monohydrate, DCC, sodium borohydride, monomethylamine, triethylamine, isopropyl amine, preferably monomethylamine.
  • deprotection reaction is selectively carried out in presence of base such as amine selected from monomethylamine, triethylamine with aqueous medium without using hydrazine hydrate.
  • the compound of formula (III) is treated with said base at a molar ratio of 1:1.5-1:5, preferably 1:2.5.
  • compound of formula (III) is treated with base at temperature 30°C-60°C, preferably 45°C-50°C.
  • the compound of formula (III) is treated with base in aqueous medium, wherein said aqueous medium is 40% solution of base in water.
  • optically active auxiliary acids used in step (b) for resolution is consisting of L-tartaric acid, ditoloyl-D-tartaric acid, and dibenzoyl-D-tartaric acid, camphor acid, camphor sulfonic acid or ⁇ -methoxy-phenylacetic acid, preferably L-tartaric acid.
  • step (c) includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide.
  • Preferably sodium or potassium carbonate is used in the reaction step (c).
  • Polar organic solvent used in step (c) is selected from the group including water, methanol, ethanol, isopropanol, n-propanol, n-butanol, methylene dichloride, ethylene dichloride, tetrahydrofuran, dioxan, acetone, acetonitrile, dimethylsulfoxide or mixture thereof.
  • the preferred solvent is ethanol. According to the most preferred embodiment of the present invention is converting S-(-)-2-amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole (I) to its pharmaceutically acceptable salts or solvates.
  • the pharmaceutically acceptable salts includes dibasic acid addition salts like hydrochloric, hydrobromic, hydroiodic, nitric, benzoic, acetic, methane sulfonic, ethane sulfonic, trifluromethane sulfonic, benzene sulfonic, p-toluene sulfonic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid and hydrate thereof, preferably dihydrochloride monohydrate.
  • the present invention provides an improved process for preparation of (S)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole of formula (II), which is an useful intermediate for the preparation of Pramipexole or (S)-2,6-amino-6-(n-propylamino)-
  • said reaction is preferably carried out at about 30 to 6O 0 C.
  • said base used in step (a) is a deprotecting reagents of phthalimido groups like hydrazine, phenyl hydrazine, sodium sulphide monohydrate, DCC, sodium borohydride, monomethylamine, triethylamine, isopropyl amine, preferably monomethylamine.
  • deprotection reaction is selectively carried out in presence of base such as amine selected from monomethylamine, triethylamine with aqueous medium without using hydrazine hydrate.
  • base such as amine selected from monomethylamine, triethylamine with aqueous medium without using hydrazine hydrate.
  • the compound of formula (III) is treated with said base at a molar ratio of 1:1.5-1:5, preferably 1 :2.5.
  • compound of formula (III) is treated with base at temperature 30°C-60°C, preferably 45°C-50°C.
  • the compound of formula (III) is treated with base in aqueous medium, wherein said aqueous medium is 40% solution of base in water.
  • optically active auxiliary acids used in step (b) for resolution is consisting of L-tartaric acid, ditoluoyl-D-tartaric acid, and dibenzoyl-D-tartaric acid, camphor acid, camphor sulfonic acid or ⁇ -methoxy-phenylacetic acid, preferably L-tartaric acid.
  • (IV) is treated with tartaric acid to provide tartrate salt of 2,6-diamino-4,5,6,7- tetrahydro-l,3-benzothiazole, which upon treatment with base provides (S)-2,6- diamino-4,5,6,7-tetrahydro-l,3-benzothiazole of formula (II).
  • alcoholic solvent used in step (iii) is selected from methanol, ethanol, propanol, isopropanol, butanol or mixtures thereof.
  • the present invention further provides an improved process for the preparation of Pramipexole of formula (I), its pharmaceutically acceptable salt, hydrates, solvates thereof, which comprises a) reacting (S)-2,6-diarnino-4,5,6,7-tetrahydro-l,3-berizothiazole of formula (II) with n-propylbromide in presence of base in a polar organic solvent to give Pramipexole of formula (I); b) optionally converting Pramipexole to its pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • Base used in step (a) includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide.
  • sodium or potassium carbonate is used in the reaction step (a).
  • Polar organic solvent used in step (a) is selected from the group including water, methanol, ethanol, isopropanol, n-propanol, n-butanol, methylene dichloride, ethyelene dichloride, tetrahydrofuran, dioxan, acetone, acetonitrile, dimethylsulfoxide or mixture thereof.
  • the preferred solvent is ethanol.
  • the pharmaceutically acceptable salts includes dibasic acid addition salts like hydrochloric, hydrobromic, hydroiodic, nitric, benzoic, acetic, methane sulfonic, ethane sulfonic, trifluromethane sulfonic, benzene sulfonic, p-toluene sulfonic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid and hydrate thereof, preferably dihydrochloride monohydrate .
  • a crystalline form of pramipexole dihydrochloride monohydrate in its preferred form characterized by x-ray powder diffraction patter having 2 ⁇ 6.50, 12.00, 12.96, 19.48,
  • the present invention further provides an improved process for the preparation of Pramipexole dihydrochloride monohydrate, which comprises (i) reacting pramipexole with solution of hydrochloric acid in C 1 -C 5 alcohols in presence of water (ii) isolating Pramipexole dihydrochloride monohydrate
  • the alcohol is selected from methanol, ethanol, isopropanolj propanol, isobutanol, butanol, tert-butanol, and pentanol, preferably isopropanol.
  • the present invention further provides an improved process for the preparation of substantially pure Pramipexole dihydrochloride monohydrate, which comprises (i) reacting pramipexole with solution of hydrochloric acid in C1-C5 alcohols (ii) isolating wet cake of Pramipexole dihydrochloride monohydrate (iii) drying wet cake of Pramipexole dihydrochloride monohydrate in tray drier at about 40 to 7O 0 C for about 30 minutes to about 7 hours, (iv) optionally cooling the dried material under airflow.
  • Alcohol is selected from methanol, ethanol, isopropanol, propanol, isobutanol, butanol, tert-butanol, pentanol, preferably isopropanol.
  • a process for the preparation of substantially pure Pramipexole dihydrochloride monohydrate includes reaction of Pramipexole with alcoholic solution of HCl, preferably isopropanolic hydrochloric acid in molar ratio of Pramipexole to HCl of about 1:1.9 to 2.3 wt/wt at about ambient temperature to reflux temperature and subsequently cooling the solution to provide wet cake, which is dried in tray drier preferably at 50 to 55 0 C for 6 hours and subsequently dried material is cooled under air flow to obtain substantially pure Pramipexole dihydrochloride monohydrate.
  • alcoholic solution of HCl preferably isopropanolic hydrochloric acid in molar ratio of Pramipexole to HCl of about 1:1.9 to 2.3 wt/wt at about ambient temperature to reflux temperature and subsequently cooling the solution to provide wet cake, which is dried in tray drier preferably at 50 to 55 0 C for 6 hours and subsequently dried material is cooled under air flow to
  • the compound of formula (VII) is treated with bromine in an alcoholic solvent, followed by treatment of the reaction mixture with thiourea to tetrahydrobenzothizole analogue via an bromo intermediate.
  • the alcoholic solvent used in step (iii) is selected from the group consisting of Ci-C 6 alcohols preferably, ethanol.
  • step (iv) The isolation of compound of formula (III) in step (iv) is achieved by centrifugation, followed by washing and drying.
  • Scheme-1 According to another aspect of the present invention there is provided a crystalline form of pramipexole dihydrochloride monohydrate in its preferred form characterized by x-ray powder diffraction patter having 20 values 6.5, 12.0, 12.9, 13.8,
  • the most preferred embodiment of the present invention is to prepare pramipexole dihydrochloride having purity 99.5% by HPLC and having impurities like tertiary amine analogues (2-amino-6,6-dipropyl-4,5,6,7-tetrahydrobenzothiazole) not more than 0.1%, diamine analogue (2,6-diamino-4,5,6,7-tetrahydrobenzothiazole) not more than 0.1% and the total impurities not 1.0%.
  • Example-1 Preparation of 2-amino-6-phthaIimido-4,5,6,7- tetrahydrobenzothiazole A) Preparation of chromic acid:
  • the reaction mass was cooled and treated with 3.36 L ethanol at 45 0 C to 25 0 C while gradual cooling.
  • the reaction mixture was further cooled to 15 0 C to 2O 0 C and treated with 0.22 L of bromine and 0.43 Kg of thiourea under stirring for 1 h.
  • the reaction mixture was heated to reflux at 75 0 C to 78 0 C for 6 hrs.
  • the reaction mixture was cooled and stirred for 1 hr at 5 0 C to 1O 0 C.
  • the product was isolated by centrifuge, washing with ethanol 0.66 L and drying under vacuum at 5O 0 C t0 55 0 C. (yield: 0.70 Kg).
  • the reaction mixture was cooled to 25 0 C to 35 0 C.
  • 40% sodium hydroxide solution (0.108 Kg in 0.27 L water) was added to adjust the constant pH 10.0 to 10.5 followed by treatment with 5.0 L methylene dichloride twice and separating the organic layer.
  • the organic layer was treated with 5.0 L of process water and stirred for 30 minutes.
  • the separated organic layer was subjected to distillation to remove methylene dichloride under vacuum.
  • 5.0 L of isopropanol was added at 4O 0 C to 45 0 C and heated up to 6O 0 C to 65 0 C.
  • Acidic isopropanol 0.440L was added to adjust the pH 7.0 to 7.5 and stirred for 1 hour.
  • the reaction mass was cooled to 25 0 C to 35°C.
  • the product was obtained by centrifuge, washing with 0.5 L of isopropanol and drying at 5O 0 C to 55 0 C followed by cooling. (Yield: 1.0 Kg)

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation de (S)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole de formule (II) utile dans la préparation du pramipexole ou du (S)-2,6-amino-6-(n-propylamino)-4,5,6,7-tétrahydrobenzothiazole de formule (I) et de ses sels ou solvates pharmaceutiquement acceptables. La présente invention concerne en outre un procédé de préparation du pramipexole et de ses sels, hydrates et solvates pharmaceutiquement acceptables.
PCT/IN2007/000017 2006-10-03 2007-01-11 Procédé de préparation de (s)-pramipexole et de ses intermédiaires WO2008041240A1 (fr)

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EP2137171A2 (fr) * 2007-03-14 2009-12-30 Knopp Neurosciences, Inc. Synthèse de benzothiazole diamines substituées et purifiées du point de vue chiral
CN104496936A (zh) * 2015-01-07 2015-04-08 海南康虹医药科技开发有限公司 一种盐酸普拉克索的制备方法
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9642840B2 (en) 2013-08-13 2017-05-09 Knopp Biosciences, Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US9763918B2 (en) 2013-08-13 2017-09-19 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
US9849116B2 (en) 2008-08-19 2017-12-26 Knopp Biosciences Llc Compositions and methods of using (R)-pramipexole
CN107573301A (zh) * 2017-11-08 2018-01-12 江苏长青农化股份有限公司 一种三环唑中间体的制备方法
CN109232471A (zh) * 2018-10-31 2019-01-18 安徽省庆云医药股份有限公司 一种盐酸普拉克索的制备方法
US10383857B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
CN110669024A (zh) * 2019-10-30 2020-01-10 福建福瑞明德药业有限公司 一种(s)-2,6-二氨基-4,5,6,7-四氢苯并噻唑*l-酒石酸盐的碱析方法
CN113816923A (zh) * 2021-09-30 2021-12-21 艾希尔（深圳）药物研发有限公司 一种普拉克索n甲基杂质的制备方法

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EP2137171A4 (fr) * 2007-03-14 2010-05-19 Knopp Neurosciences Inc Synthèse de benzothiazole diamines substituées et purifiées du point de vue chiral
AU2008224844B2 (en) * 2007-03-14 2012-08-09 Knopp Neurosciences, Inc. Synthesis of chirally purified substituted benzothiazole diamines
EP2137171A2 (fr) * 2007-03-14 2009-12-30 Knopp Neurosciences, Inc. Synthèse de benzothiazole diamines substituées et purifiées du point de vue chiral
US10179774B2 (en) 2007-03-14 2019-01-15 Knopp Biosciences Llc Synthesis of chirally purified substituted benzothiazole diamines
US9849116B2 (en) 2008-08-19 2017-12-26 Knopp Biosciences Llc Compositions and methods of using (R)-pramipexole
US10208003B2 (en) 2011-12-22 2019-02-19 Knopp Biosciences Llc Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9956206B2 (en) 2013-02-28 2018-05-01 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US10285981B2 (en) 2013-02-28 2019-05-14 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US10828284B2 (en) 2013-07-12 2020-11-10 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US11612589B2 (en) 2013-07-12 2023-03-28 Areteia Therapeutics, Inc. Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US10383857B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US11026928B2 (en) 2013-07-12 2021-06-08 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US10383856B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US10980783B2 (en) 2013-07-12 2021-04-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US9642840B2 (en) 2013-08-13 2017-05-09 Knopp Biosciences, Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
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CN110669024A (zh) * 2019-10-30 2020-01-10 福建福瑞明德药业有限公司 一种(s)-2,6-二氨基-4,5,6,7-四氢苯并噻唑*l-酒石酸盐的碱析方法
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